study of a new anti-hiv drug, t-20, in hiv-infected children

Conditions: HIV Infections

Summary: the purpose of this study is to determine the best dose of t-20, a new anti-hiv drug, to treat hiv-infected children. t-20, unlike other anti-hiv medications, lessens the ability of hiv to infect certain cells (t cells) in the body. doctors hope to better treat hiv by adding t-20 to anti-hiv drug combinations that include 1 or 2 nucleoside reverse transcriptase inhibitors (nrtis) plus a nonnucleoside reverse transcriptase inhibitor (nnrti) and/or a protease inhibitor (pi).

t-20 is the first drug to be developed which specifically inhibits the function of the gp41 transmembrane glycoprotein. by inhibiting the essential protein-protein surface interaction, t-20 is able to block the process of virus-to-host cell membrane fusion. combination antiretroviral regimens (reverse transcriptase inhibitors plus pis) have benefited many hiv patients, but heavily pretreated patients often develop multi-drug resistance via multiple gene mutations. a pharmacologic agent, such as t-20, that is effective at an alternative point in the virus replication cycle will make a valuable addition to the treatment of hiv infection. this phase i/ii open-label, dose-escalating, randomized study is divided into 2 parts. patients may participate in part a and/or part b. part a (single dosing): 12 patients are sequentially assigned to receive 1 of 3 doses of t-20 given once on day 0 by sc injection into the abdomen, deltoid area, or anterior aspect of the thigh and once on day 1 by iv infusion. provided safety criteria are met, patients who complete part a, or new enrollees who did not participate in part a, enroll in part b. doses for part b are determined by pharmacokinetic data obtained in part a. \[as per amendment 4/20/00: current data has now projected a pediatric dose. each child will move to chronic dosing in part b provided the child has no grade 3 or higher toxicity to study drug through day 7 in part a.\] part b (multiple dosing): patients are randomly assigned to 1 of 3 dose cohorts to receive 24 weeks \[as per amendment 12/7/00: 48 weeks\] of treatment (optional extension to 48 weeks \[as per amendment 12/7/00: 96 weeks\]) with bid sc injections of t-20. cohort 1 receives the dose identified in part a (dose 1) as the lowest dose that is well tolerated and that achieves the target trough plasma concentration. cohort 2 receives the next higher dose from dose 1 (dose 2). cohort 3 receives either dose 1 or dose 2, depending on the tolerability and antiviral activity of each dose. \[as per amendment 4/20/00: cohort 1 receives 30 mg/m2 sc bid (dose 1); cohort 2 receives 60 mg/m2 sc bid (dose 2); and cohort 3 receives dose 1 or 2 sc bid.\] on day 7 of t-20 dosing, children begin a new antiretroviral therapy regimen chosen by the site investigator based on study parameters. (abacavir and amprenavir are not allowed for this regimen.) \[as per amendment 1/6/00: abacavir and amprenavir are now allowed.\] the first injection will be given in the clinic and a parent/guardian will be trained to give successive injections. \[as per amendment 4/20/00: the 2 doses given prior to obtaining trough levels on days 1 and 7 must be directly observed by medical personnel.\] patients undergo clinical and laboratory evaluations to monitor viral load, hiv-related symptoms, and pharmacokinetics at time points throughout the study. patients participating in part a are evaluated at the clinic on days 0, 1, and 7. patients participating in part b are evaluated at the clinic 6 times during the first 3 weeks and then every 4 weeks through week 24. \[as per amendment 12/7/00: patients participating in part b are evaluated at the clinic 6 times during the first 3 weeks, every 4 weeks through week 24, and then every 8 weeks through week 48.\]

Eligibility criteria:
inclusion criteria children may be eligible for this study if they: * are 3 to 12 years old (consent of parent or guardian required). * are hiv-positive. * are receiving combination anti-hiv therapy. he/she must have been taking this combination for at least 16 weeks, and it must include either 2 nrtis alone or 2 nrtis plus either an nnrti or a pi. (this study has been changed. this no longer has to be a child's first anti-hiv drug combination.) * have a viral load greater than 10,000 copies/ml while taking this anti-hiv drug combination. * have never received treatment with a pi or an nnrti. (one or two doses are allowed.) * have never taken at least 1 nrti. exclusion criteria children will not be eligible for this study if they: * are receiving treatment for an opportunistic (aids-related) or serious bacterial infection at the time of study entry. * are receiving chemotherapy for cancer. * have certain serious diseases (other than hiv) or conditions. * have received or are currently receiving certain medications. * are pregnant.

Keywords: injections, intravenous injections, subcutaneous drug therapy, combination hiv protease inhibitors membrane fusion reverse transcriptase inhibitors anti-hiv agents viral load peptide t20